Summary Salmonella and other pathogens use host microbiota-produced molecular hydrogen (H2) to grow within the host; they do so via conserved nickel-containing hydrogenase enzymes. A new exploratory approach is proposed to assess the ability of natural histidine- and cysteine-containing metal-binding peptides to combat salmonellosis. The rationale is based on the effectiveness of nickel chelating chemicals to attenuate Salmonella hydrogenase expression and even salmonellosis in mice. However, the known chelators are toxic to the animal. Instead, small peptides that have inherently high capacity for nickel binding will be assessed first for their ability to inhibit H2 dependent growth of the pathogen in the lab and then within the animal. The degree of inhibition of H2-dependent growth by nickel deprivation will be assigned to individual hydrogen-utilizing hydrogenases by studying mutant strains. The molecular nature of the chelator, including use of Ni-binding domain fusions, as well as the nanoparticle host delivery regimes will be studied to fully assess the salmonella-inhibitory affects. Testing of truncated and fused versions composed of identified Ni-sequestering domains is expected to improve chelator (nickel-binding) effectiveness per mg of peptide, while encapsulating them in biodegradable polymeric micelles is expected to promote their gastric survival so their effectiveness in vivo can be assessed in an exploratory way. For in vivo testing, peptide-based chelation in the small intestine where Salmonella growth is rapid and dependent on H2 via an identified Ni-hydrogenase is desired. The work is expected to apply to growth attenuation of nickel-requiring enteric pathogens, including Salmonella, Shigella, enterotoxigenic E. coli, and Campylobacter, but the new metal chelator development may apply to many areas of medicine.